A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation.

Adult Aged Animals Casein Kinase II / genetics Cell Differentiation Cleidocranial Dysplasia / genetics Core Binding Factor Alpha 1 Subunit / metabolism Female Gene Deletion Haploinsufficiency / genetics Hindlimb / metabolism Humans Male Mice, Inbred C57BL Middle Aged Ossification, Heterotopic / genetics Osteoblasts / metabolism Osteogenesis Phosphorylation Protein Stability RNA, Messenger / genetics Ubiquitin-Specific Peptidase 7 / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 05 2020
Historique:
received: 02 03 2019
accepted: 10 04 2020
entrez: 10 5 2020
pubmed: 10 5 2020
medline: 6 8 2020
Statut: epublish

Résumé

The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.

Identifiants

DOI: 10.1038/s41467-020-16038-6 PMID: 32385263 PMC: PMC7210266
pubmed: 32385263
doi: 10.1038/s41467-020-16038-6
pii: 10.1038/s41467-020-16038-6
pmc: PMC7210266
doi:

Substances chimiques

Core Binding Factor Alpha 1 Subunit 0
RNA, Messenger 0
Casein Kinase II EC 2.7.11.1
USP7 protein, human EC 3.4.19.12
Ubiquitin-Specific Peptidase 7 EC 3.4.19.12

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2289

Subventions

Organisme : NIAMS NIH HHS
ID : R21 AR072836
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR068983
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR057374
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001454
Pays : United States
Organisme : NIH HHS
ID : DP5 OD021351
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR075585
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR073331
Pays : United States
Organisme : NCATS NIH HHS
ID : UG3 TR002617
Pays : United States

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Auteurs

Jung-Min Kim (JM)

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.

Yeon-Suk Yang (YS)

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.

Kwang Hwan Park (KH)

Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, South Korea.

Xianpeng Ge (X)

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.

Ren Xu (R)

State Key Laboratory of Cellular Stress Biology, Xiamen University, Fujian, China.
ORCID: 0000-0001-6578-4553

Na Li (N)

State Key Laboratory of Cellular Stress Biology, Xiamen University, Fujian, China.

Minkyung Song (M)

Department of integrative biotechnology, Sungkyunkwan University, Suwon, South Korea.

Hyunho Chun (H)

Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.

Seoyeon Bok (S)

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Julia F Charles (JF)

Department of Orthopedics and Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-5875-314X

Odile Filhol-Cochet (O)

INSERM U1036, pour le Vivant/Biologie du Cancer et de l'Infection, Commissariat à l'Énergie Atomique et aux Énerigies Alternatives Grenoble, Grenoble, France.
ORCID: 0000-0003-1964-7958

Brigitte Boldyreff (B)

KinaseDetect ApS, 6340, Krusaa, Denmark.

Teresa Dinter (T)

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Paul B Yu (PB)

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0003-2145-4944

Ning Kon (N)

Institute of Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, NY, USA.

Wei Gu (W)

Institute of Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
ORCID: 0000-0002-1480-2368

Takeshi Takarada (T)

Department of Regenerative Science, Okayama University Graduate School of Medicine, Okayama, Japan.
ORCID: 0000-0002-2363-7704

Matthew B Greenblatt (MB)

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. mag3003@med.cornell.edu.

Jae-Hyuck Shim (JH)

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. jaehyuck.shim@umassmed.edu.
Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA. jaehyuck.shim@umassmed.edu.
ORCID: 0000-0002-4947-3293

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Eucaryotes › Animaux › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Casein Kinases › Casein Kinase II › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations de l'appareil locomoteur › Malformations crâniofaciales › Dysostose cleido-crânienne héréditaire › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription CBF › Sous-unités alpha du facteur CBF › Sous-unité alpha 1 du facteur CBF › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Délétion de séquence › Délétion de gène › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › A RUNX2 stabilization pathway mediates...
questionsmedicales.fr › Structures anatomiques de l'animal › Membre pelvien › A RUNX2 stabilization pathway mediates...
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